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FIGURE 7 Stimulation of steroidogenesis in a zona fasciculata cell of the adrenal cortex by ACTH. The rate-determining reaction is the conversion of cholesterol to pregnenolone, which requires mobilization of cholesterol from its storage droplet and transfer to the P450scc (side-chain cleavage enzyme) on the inner mitochondrial membrane. See text for discussion. ACTH may also increase cholesterol uptake by increasing the number or affinity of low density lipoprotein (LDL) receptors. as, stimulatory a-subunit of the guanine nucleotide-binding protein; AC, adenylyl cyclase, ßy, ßy-subunits of the guanine nucleotide-binding protein; StAR, steroid acute regulatory protein.

FIGURE 7 Stimulation of steroidogenesis in a zona fasciculata cell of the adrenal cortex by ACTH. The rate-determining reaction is the conversion of cholesterol to pregnenolone, which requires mobilization of cholesterol from its storage droplet and transfer to the P450scc (side-chain cleavage enzyme) on the inner mitochondrial membrane. See text for discussion. ACTH may also increase cholesterol uptake by increasing the number or affinity of low density lipoprotein (LDL) receptors. as, stimulatory a-subunit of the guanine nucleotide-binding protein; AC, adenylyl cyclase, ßy, ßy-subunits of the guanine nucleotide-binding protein; StAR, steroid acute regulatory protein.

of StAR protein. Early studies of how ACTH increases steroidogenesis revealed a puzzling requirement for protein synthesis that ultimately led to the discovery of the StAR protein. It appears that ACTH increases StAR protein by stimulating its synthesis on preexisting mRNA templates and by promoting gene transcription (Fig. 7). Thus the immediate actions of ACTH accelerate the delivery of cholesterol to P450scc to form pregneno-lone. Once pregnenolone is formed, remaining steps in steroid biosynthesis can proceed without further intervention from ACTH, although some evidence suggests that ACTH may also speed up some later reactions in the biosynthetic sequence. With continued stimulation, ACTH, acting through cyclic AMP and protein kinase A, also stimulates transcription of the genes encoding the P450 enzymes (P450scc, P450c21, P450c17, and P450c11j) and the LDL receptor responsible for uptake of cholesterol.

ACTH is the only hormone known to control synthesis of the adrenal androgens. These 19-carbon steroids are produced primarily in the zona reticularis. Their production is limited first by the rate of conversion of cholesterol to pregnenolone and subsequently by cleavage of the carbon 17-20 bond. As already mentioned, P450c17, the same enzyme that catalyzes a-hydroxylation of carbon 17 of cortisol also catalyzes the second oxidative reaction at carbon 17 (17,20-lyase) that removes the C20,21 side chain. Some evidence suggests that the lyase reaction is increased by phos-phorylation of the P450c17, and other studies suggest that androgen production is driven by the capacity of reticularis cells to deliver reducing equivalents to the reaction. Little or no androgen is produced in young children whose adrenal glands contain only a rudimentary zona reticularis. The reticularis with its unique complement of enzymes develops shortly before puberty. The arrival of puberty is heralded by a dramatic increase in production of the adrenal androgens, principally dehydroepiandrosterone sulfate (DHEAS), which are responsible for growth of pubic and axillary hair. Secretion of DHEAS gradually rises to reach a maximum by age 20-25, and thereafter declines. This pattern of androgen secretion is quite different from the pattern of cortisol secretion and therefore appears to be governed by other factors than simply the ACTH-dependent rate of pregnenolone formation. These findings have led some investigators to propose separate control of androgen production, possibly by another, as yet unidentified pituitary hormone, but to date no such hormone has been found. It is important to emphasize that increased stimulation of both the fasciculata and the reticularis by ACTH can profoundly increase adrenal androgen production.

Effects of ACTH on the adrenal cortex are not limited to accelerating the rate-determining step in steroid hormone production. ACTH either directly or indirectly also increases blood flow to the adrenal glands and thereby provides not only the needed oxygen and metabolic fuels but also increased capacity to deliver newly secreted hormone to the general circulation. ACTH maintains the functional integrity of the inner zones of the adrenal cortex: Absence of ACTH leads to atrophy of these two zones, while chronic stimulation increases their mass.

Stimulation with ACTH increases steroid hormone secretion within 1-2 min, and peak rates of secretion are seen in about 15 min. Unlike other glandular cells, steroid-producing cells do not store hormones, and hence biosynthesis and secretion are components of a single process regulated at the step of cholesterol conversion to pregnenolone. Because steroid hormones are lipid soluble they can diffuse through the plasma membrane and enter the circulation through simple diffusion down a concentration gradient. Even under basal conditions, cortisol concentrations are more than 100 times higher in fasciculata cells than in plasma. It is not surprising, therefore, that biosynthetic intermediates may escape into the circulation during intense stimulation. Human adrenal glands normally produce about

20 mg of cortisol, about 2 mg of corticosterone, 10-15 mg of androgens, and about 150 mg of aldosterone each day, but with sustained stimulation they can increase this output manyfold.

Regulation of Aldosterone Synthesis

The regulation of aldosterone synthesis is considerably more complex than that of the glucocorticoids and is not completely understood. Although cells of the zona glomerulosa express ACTH receptors and ACTH is required for optimal secretion, ACTH is not an important regulator of aldosterone production in most species. Angiotensin II, an octapeptide whose production is regulated by the kidney (see later discussion and Chapter 29) is the hormonal signal for increased production of aldosterone (Fig. 8). The cellular events entrained by angiotensin II are not as well established as those described for ACTH. Like ACTH, angiotensin II reacts with specific G-protein-coupled receptors, but angioten-sin II does not activate adenylyl cyclase or use cyclic AMP as its second messenger. Instead, it acts through inositol trisphosphate (IP3) and calcium to promote the formation of pregnenolone from cholesterol. The ligand-bound angiotensin receptor associates with Gaq and activates phospholipase C to release IP3 (see Chapter 2)

CAM Kinase

Ca2+

CAM Kinase II -StAR mRNA I pregnenolone

CAM Kinase

Ca2+

mitochondrion

FIGURE 8 Stimulation of aldosterone synthesis by angiotensin II (AII). AII accelerates the conversion of cholesterol to pregnenolone and 11-deoxycorticosterone to aldosterone. aq, ßy, subunits of the guanine nucleotide-binding protein; PLC, phospholipase C; DAG, diacylglycerol; IP3, inositol trisphosphate; PKC, protein kinase C; CAM kinase II, calcium-calmodulin-dependent protein kinase II; StAR, steroid acute regulatory protein. High concentrations of potassium (K+) in blood also increase aldosterone synthesis and secretion by increasing intracellular calcium secondary to partial membrane depolarization.

mitochondrion

FIGURE 8 Stimulation of aldosterone synthesis by angiotensin II (AII). AII accelerates the conversion of cholesterol to pregnenolone and 11-deoxycorticosterone to aldosterone. aq, ßy, subunits of the guanine nucleotide-binding protein; PLC, phospholipase C; DAG, diacylglycerol; IP3, inositol trisphosphate; PKC, protein kinase C; CAM kinase II, calcium-calmodulin-dependent protein kinase II; StAR, steroid acute regulatory protein. High concentrations of potassium (K+) in blood also increase aldosterone synthesis and secretion by increasing intracellular calcium secondary to partial membrane depolarization.

and diacylglycerol (DAG) from membrane phosphati-dylinositol bisphosphate. Gaq may also interact directly with potassium channels and cause them to close. The resulting depolarization of the membrane opens voltage-gated calcium channels and allows calcium to enter. Simultaneously, the fty-subunits directly activate calcium channels, thus further promoting calcium entry. Intra-cellular calcium concentrations are also increased by interaction of IP3 with its receptor in the endoplasmic reticulum to release stored calcium. Increased intracel-lular calcium activates a calmodulin-dependent protein kinase that promotes transfer of cholesterol into the mitochondria by increasing synthesis ofthe StAR protein in the same manner as described for protein kinase A in fasciculata cells. The increase in cytosolic calcium in turn raises the intramitochondrial calcium concentration and stimulates P450c11AS, which catalyzes the critical final reactions in aldosterone synthesis. The DAG that is released by activation of phospholipase C activates protein kinase C, but the role of this enzyme is uncertain. It may augment synthesis of StAR protein, and it may participate in calcium channel activation. Protein kinase C may also play an important role in mediating the hypertrophy of the zona glomerulosa seen after prolonged stimulation of the adrenal glands with angiotensin II.

Cells of the zona glomerulosa are exquisitely sensitive to changes in concentration of potassium in the extracellular fluid and adjust aldosterone synthesis accordingly. An increase of as little as 0.1 mM in the concentration of potassium, which corresponds to a change of only about 2-3%, may increase aldosterone production by as much as 35%. Increased extracellular potassium depolarizes the plasma membrane and activates voltage-gated calcium channels. The resulting increase in intracellular calcium stimulates aldosterone synthesis as already described. The rate of aldosterone secretion can also be affected by the concentration of sodium in the extracellular fluid, but relatively large changes are required. A decline in sodium concentration increases sensitivity to angiotensin II and potassium, but direct effects of sodium on glomerulosa cells are relatively unimportant except in extreme cases of sodium depletion. However, sodium profoundly affects aldos-terone synthesis indirectly through its influence on production of angiotensin II as described later and in Chapter 29.

Synthesis and secretion of aldosterone are also negatively regulated by the atrial natriuretic factor (ANF) secreted primarily by the cardiac atria. This hormone and its role in normal physiology are discussed in Chapter 29. ANF receptors have intrinsic guanylyl cyclase activity and, when bound to ANF, catalyze the conversion of guanosine triphosphate to cyclic guanosine monophosphate (cyclic GMP). Precisely how an increase in cyclic GMP antagonizes the actions of angiotensin and potassium on aldosterone synthesis has not been established. Cyclic GMP is known to activate the enzyme cyclic AMP phosphodiesterase, and may thereby lower basal levels of cyclic AMP, or it may act through stimulating cyclic GMP-dependent protein kinase.

Adrenal Steroid Hormones in Blood

Adrenal cortical hormones are transported in blood bound to a specific plasma protein, corticosteroid binding globulin (CBG), which is also called transcortin, and to a lesser extent to albumin. Like albumin, CBG is synthesized and secreted by the liver, but its concentration of mM in plasma is only about 1000th that of albumin. CBG is a glycoprotein with a molecular weight of about 58,000, and is a member of the serine proteinase inhibitor (SERPIN) superfamily of proteins. It has a single steroid hormone binding site whose affinity for glucocorticoids is nearly 20 times higher than for aldosterone. About 95% of the glucocorticoids and about 60% of the aldosterone in blood are bound to protein. Under normal circumstances the concentration of free or unbound cortisol in plasma is about 100 times that of aldosterone. Probably because they circulate bound to plasma proteins, adrenal steroids have a relatively long half-life in blood: 1.5-2 hr for cortisol, and about 15 min for aldosterone.

Metabolism and Excretion of Adrenal Cortical Hormones

Because mammals cannot degrade the steroid nucleus, elimination of steroid hormones is achieved by inactivation through metabolic changes that make them unrecognizable to their receptors. Inactivation of glucocorticoids occurs mainly in liver and is achieved primarily by reduction of the A ring and its keto group at position 3. Conjugation of the resulting hydroxyl group on carbon 3 with glucuronic acid or sulfate increases water solubility and decreases binding to CBG so the steroid can now pass through renal glomerular capillaries and be excreted in the urine. The major urinary products of steroid hormone degradation are glucuronide esters of 17-hydroxycorticosteroids (17-OHCS) derived from cortisol, and 17-ketosteroids (17-KS) derived from glucocorticoids and androgens. Because recognizable hormonal products can be identified in the urine, it is possible to estimate the daily secretory rate of steroid hormones by the noninvasive technique of analyzing urinary excretory products.

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